Antihypertensive 4-thiazolidinecarboxylic acids (substituted phenyl derivatives)

ABSTRACT

Derivatives of 4-thiazolidinecarboxylic acid which have the general formula   &lt;IMAGE&gt;   are useful in compositions as antihypertensive agents.

This is division of application Ser. No. 23,397 filed Mar. 23, 1979.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to derivatives of 4-thiazolidinecarboxylic acid and salts thereof which are useful as antihypertensive agents. These compounds are represented by the formula ##STR2## wherein

R¹ is mercapto-lower alkyl, acylmercapto-lower alkyl, higher alkyl, cycloalkyl, aralkyl, phenyl, furyl, thienyl, pyridyl, naphthyl, substituted higher alkyl, substituted cycloalkyl, substituted aralkyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substituent(s) is lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylenedioxy, acyloxy, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino or carboxy;

R¹ may be benzofuryl, benzothienyl, indolyl, substituted benzofuryl, substituted benzothienyl or substituted indolyl wherein the substituent(s) is lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylenedioxy, acyloxy, acylmercapto, halogen, nitro, amino, lower alkylamino, acylamino or carboxy;

the substituent(s) may be hydroxy-lower alkyl;

R² is hydrogen or benzoyl;

A is straight or branched alkylene with 1 to 3 carbon atoms (e.g. --CH₂ --, --CH(CH₃)--, --CH₂ CH₂ --, --CH(CH₃)CH₂ --); in the formula

lower alkyl or alkylene is saturated or unsaturated, straight or branched chain with 1 to 6 carbon atoms;

higher alkyl is saturated or unsaturated, straight or branched chain with 7 to 20 carbon atoms;

acyl is acetyl, pivaloyl, substituted or unsubstituted benzoyl, benzyloxycarbonyl, etc.;

aralkyl is benzyl, etc.;

and salts thereof. The same shall be applied hereinafter.

The compounds of formula I of this invention are mercaptoacylamino acids and S-substituted mercaptoacylamino acids. Mercaptoacylamino acids have an inhibitory activity against angiotensin I-converting enzyme and therefore they are useful as antihypertensive agents. S-Substituted mercaptoacylamino acids release mercaptoacylamino acid by enzymatic and/or chemical cleavage when administered to men or animals.

The compounds of formula I can be produced by the following methods.

An acid of the formula ##STR3## is reacted with an alkanoic acid or an alkanoyl halide of the formula

    R.sup.4 S--A--CO--Y                                        (III)

by one of the known procedures wherein the compound III is activated prior to reaction with the acid II, forming a mixed anhydride, symmetrical anhydride, acid chloride, active ester, etc. to produce the compounds of the formula I. The resulting compound can then be converted to the compound of formula I, wherein R² is hydrogen, by hydrolysis or reduction (e.g. acid treatment with hydrochloric acid, p-toluenesulfonic acid, etc.; alkali treatment with sodium hydroxide, ammonia, etc.; catalytic reduction with palladium-carbon, etc.; alkali metal treatment in liquid ammonia).

In another way, the compounds of formula I are produced by reacting an acid of formula II with a haloalkanoic acid or a haloalkanoyl halide of the formula

    X--A--CO--Y                                                (IV)

and by reacting the resulting haloacid of the formula ##STR4## with thiobenzoic acid or benzylmercaptan. The resulting compound can then be converted to the compound of formula I, wherein R² is hydrogen, by hydrolysis or reduction in the same manner as above. In the formulas,

R³ is acylmercapto-lower alkyl, higher alkyl, cycloalkyl, aralkyl, phenyl, furyl, thienyl, pyridyl, naphthyl, substituted higher alkyl, substituted cycloalkyl, substituted aralkyl, substituted phenyl, substituted furyl, substituted thienyl, substituted pyridyl or substituted naphthyl wherein the substituent(s) is lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, acyloxy, acylmercapto, halogen, nitro, lower alkylamino, acylamino or carboxy;

the substituent(s) may be hydroxy-lower alkyl;

R⁴ is benzoyl or benzyl;

R⁴ may be alkyl- or phenylcarbamoyl;

X is halogen (e.g. bromine or chlorine);

Y is hydroxy or halogen.

The compounds of formula I synthesized by the above methods can form the conventional salts to be generally used as medicine such as sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, diethylamine salt, triethanolamine salt, etc.

The compounds of formula I have the stereoisomers which are within the limit of this invention because they have one or more asymmetric carbon atoms. The NMR spectrum (DMSO-d₆) of 3-(S-benzoyl)-3-mercaptopropanoyl)-2-phenyl-4-thiazolidinecarboxylic acid (Compound 15) at 23° C. has one pair of signals of C(4)-methine proton at 5.45 ppm (dd, J=4.0, 6.0 Hz) and 4.84 ppm (dd, J=7.5, 8.0 Hz) and another pair of signals of C(2)-methine proton at 6.46 ppm (singlet) and 6.26 ppm (singlet), while at 100° C. the signal of C(4)-methine proton at 5.00 ppm (dd, J=5.0, 6.0 Hz) and the signal of C(2)-methine proton at 6,32 ppm (singlet). This compound has the same spectrum pattern as (2R, 4R)-3-acetyl-2-phenyl-4-thiazolidinecarboxylic acid of which the configuration was determined by R. Parthasarathy et al. [J. Am. Chem. Soc., 98, 6634 (1976)]. Therefore the configuration of Compound 15 proved to be (2R, 4R). In Tables I and II, "a" and "b" of Compd. No. represent diastereoisomers that one configuration is (2R, 4R) and another is (2S, 4R).

Examples are shown below, although this invention is not limited to these examples.

EXAMPLE 1 (4R)-3-[(2S)-S-Benzoyl-3-mercapto-2-methylpropanoyl]-2-(4-methylphenyl)-4-thiazolidinecarboxylic acid (Compound 21)

4.5 g of (4R)-2-(4-methylphenyl)-4-thiazolidinecarboxylic acid and 4.3 g of sodium carbonate are dissolved in 25 ml of water and 4.9 g of (2S)-S-benzoyl-3-mercapto-2-methylpropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and acidified with dilute hydrochloric acid. The produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give oil. The produced oil is purified by silica gel column chromatography to give the titled compound, yield 4.0 g (48%), mp. 131°-132° C. (ethyl acetatehexane), [α]_(D) ²⁶ +117.6° (c=1.0, methanol).

IR (nujol, cm⁻¹) 1755, 1650, 1610, 915.

Analysis (C₂₂ H₂₃ NO₄ S₂): Calcd: C, 61.52; H, 5.40; N, 3.26 Found: C, 61.60; H, 5.42; N, 3.26

EXAMPLE 2 (4R)-3-(S-Benzoyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (Compound 45)

11.3 g of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid and 13.2 g of triethylamine are dissolved in 200 ml of dehydrated acetone and 11.7 g of S-benzoyl-3-mercaptopropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour. 4 N Hydrochloric acid in ether is added to this mixture and the precipitate is filtered. The filtrate is concentrated in vacuo and the obtained oil is dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give the titled compound, yield 12 g (58%), mp. 100.5°-101° C. (dec.) (ethyl acetatebenzene), [α]_(D) ²⁶ +130.8° (c=1.0, methanol).

IR (nujol, cm⁻¹) 3460, 1760, 1663, 1580, 910.

Analysis (C₂₀ H₁₉ NO₅ S₂.C₆ H₆): Calcd: C, 63.01; H, 5.08; N, 2.83 Found: C, 63.01; H, 5.07; N, 2.61

EXAMPLE 3 (4R)-3-(S-Benzoyl-3-mercaptopropanoyl)-2-(2-thienyl)-4-thiazolidinecarboxylic acid (Compound 88)

10.8 g of (4R)-2-(2-thienyl)-4-thiazolidinecarboxylic acid and 10.6 g of sodium carbonate are dissolved in 100 ml of water and 8.6 g of 3-bromopropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 2 hours. To this reaction solution, 8.8 g of potassium thiobenzoate is added and stirred at room temperature for 1 hour. The solution is acidified with dilute hydrochloric acid and the produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the titled compound, yield 11.6 g (57%), mp. 141°-143° C. (benzene), [α]_(D) ²⁵ +107.7° (c=1.0, methanol).

IR (nujol, cm⁻¹) 1745, 1645, 1610, 917.

Analysis (C₁₈ H₁₇ NO₄ S₃): Calcd: C, 53.05; H, 4.20; N, 3.44 Found: C, 52.93; H, 4.01; N, 3.31

EXAMPLE 4 (4R)-3-[(2S)-S-Benzoyl-3-mercapto-2-methylpropanoyl]-2-(2-thienyl)-4-thiazolidinecarboxylic acid (Compound 90)

11.2 g of (2S)-S-benzoyl-3-mercapto-2-methylpropanoic acid and 5.1 g of triethylamine are dissolved in 100 ml of dehydrated tetrahydrofuran. To this solution, 6.8 g of isobutyl chloroformate is added dropwise while stirring at the temperature maintained -5° C. After the addition, the mixture is stirred at room temperature for 10 minutes. To this solution, 10.8 g of (4R)-2-(2-thienyl)-4-thiazolidinecarboxylic acid and 5.1 g of triethylamine dissolved in the mixed solution of 5 ml of tetrahydrofuran and 15 ml of water are added. The mixture is stirred at room temperature for 30 minutes. To this reaction mixture, 200 ml of water is added and the mixture is extracted with ethyl acetate. The aqueous layer is acidified with dilute hydrochloric acid and the produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the titled compound, yield 10.3 g (49%), mp. 136°-137° C. (benzene), [α]_(D) ²⁵ +79.6° (c=1.0, methanol).

IR (nujol, cm⁻¹) 1750, 1650, 1620, 920.

Analysis (C₁₉ H₁₉ NO₄ S₃): Calcd: C, 54.14; H, 4.54; N, 3.32, Found: C, 54.19; H, 4.36; N, 3.26.

EXAMPLE 5 (4R)-2-(2-Hydroxyphenyl)-3-(3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid (Compound 46)

To 4.2 g of (4R)-3-(S-benzoyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 40 ml of conc. ammonia is added and this solution is stirred at room temperature for 1 hour. Excess ammonia is removed in vacuo and the by-product, benzamide, is extracted with ethyl acetate. The aqueous layer is acidified with dilute hydrochloric acid and the produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give the titled compound, yield 2.2 g (70%), mp. 146°-148° C. (ethyl acetate), [α]_(D) ²⁶ +176° (c=1.0, methanol).

IR (nujol, cm⁻¹) 3390, 1724, 1626.

Analysis (C₁₃ H₁₅ NO₄ S₂): Calcd: C, 49.82; H, 4.82; N, 4.47, Found: C, 49.74; H, 4.88; N, 4.32.

Tables I, II and III show various compounds and physical constants including the compounds specified in the examples.

    TABLE I       ##STR5##              Analysis (%)        Calcd.   Method of (1.2,MeOH    (Found)      Comp.  prepn. Yield  Recrystn. [α].sub.D deg. .BHorizBrace. No.      R.sup.1 R.sup.5 R.sup.2 (Examp. No.) (%) mp. (°C.) solvent (c,      solv., °C.) Formula       C H N                                                       1       ##STR6##       Me COPh 2 84 oil119-120 c-hexane -104.3(1.0, MeOH, 25)-61.1(1.0, MeOH,      25) C.sub.24 H.sub.33 NO.sub.4 S.sub.2 C.sub.24 H.sub.33 NO.sub.4      S.sub.2.C.sub.12 H.sub.23 N* 67.04(67.21) 8.75(8.84) 4.34(4.31)  2       ##STR7##       Me H 5 66 oil  -68.5(1.1, MeOH, 25) C.sub.17 H.sub.29 NO.sub.3 S.sub.2       3       ##STR8##       Me COPh 2 81 oil128-133.5 EtOHether -56.5 (1.0, MeOH, 25) C.sub.21      H.sub.27 NO.sub.4 S.sub.2 C.sub.21 H.sub.27 NO.sub.4 S.sub.2.C.sub.12      H.sub.23 N* 65.74(65.85) 8.36 (8.41) 4.65(4.59)        4      ##STR9##       Me H 5 76 amorph.  -72.2(1.0, MeOH, 25) C.sub.14 H.sub.23 NO.sub.3      S.sub.2   5a (CH.sub.2).sub.2 SAc H COPh 2 27 oil EtOH -79.1 C.sub.18      H.sub.21 NO.sub.5 S.sub.3 59.18 7.28 4.60       186-188  (1.0, MeOH, 25)      C.sub.18 H.sub.21 NO.sub.5 S.sub.3.C.sub.12 H.sub.23 N* (59.05) (7.28)      (4.56) 5b (CH.sub.2).sub.2 SAc H COPh 2 23 oil EtOAc -33.3 C.sub.18      H.sub.21 NO.sub.5 S.sub.3 59.18 7.28 4.60       112-114  (1.0, MeOH, 25)      C.sub.18 H.sub.21 NO.sub.5 S.sub.3.C.sub.12 H.sub.23 N* (59.01) (7.25)      (4.53) 6a (CH.sub.2).sub.2 SH H H 5 63 138-141.5 EtOAc -166.3 C.sub.9      H.sub.15 NO.sub.3 S.sub.3 38.41 5.37 4.98         (1.0, MeOH, 25)      (38.57) (5.32) (4.92) 6b (CH.sub.2).sub.2 SH H H 5 52 97.5-102.5  -52.6      C.sub.9 H.sub.15 NO.sub.3       S.sub.3         (1.0, MeOH, 25) 7a (CH.sub.2).sub.2 SAc Me COPh 2 21      oil  -99.3 C.sub.19 H.sub.23 NO.sub.5 S.sub.3 59.78 7.44 4.50      178.5-189  (1.0, MeOH, 25) C.sub.19 H.sub.23 NO.sub.5 S.sub.3.C.sub.12      H.sub.23 N* (59.72) (7.43) (4.45) 7b (CH.sub.2).sub.2 SAc Me COPh 2  oil      EtOhether -70.6 C.sub.19 H.sub.23 NO.sub.5 S.sub.3 59.78 7.44 4.50      157-158  (1.0, MeOH, 25) C.sub.19 H.sub.23 NO.sub.5 S.sub.3.C.sub.12      H.sub.23 N* (59.66) (7.45) (4.43) 8a (CH.sub.2).sub.2 SH Me H 5 75      141-142 EtOAc -175.4 C.sub.10 H.sub.17 NO.sub.3 S.sub.3.1/4C.sub.4      H.sub.8 O.sub.2 ** 41.62 6.03 4.41         (1.0, MeOH, 25)  (41.31)      (5.82) (4.71) 8b (CH.sub.2).sub.2 SH Me H 5 71 oil  -117.5 C.sub.10      H.sub.17 NO.sub.3 S.sub.3         (1.0, MeOH, 25) 9a CH.sub.2 PH Me COPh      2 38 190 dec. EtOAc -113.2 C.sub.22 H.sub.23 NO.sub.4 S.sub.2      (1.3, MeOH, 28) 9b CH.sub.2 Ph Me COPh 2 30 143.5- EtOAcc-hexane -147.8      C.sub.22 H.sub.23 NO.sub.4 S.sub.2 61.52 5.40 3.26        149.5  (1.2,      MeOH, 28)  (61.55) (5.42) (3.27) 10a CH.sub.2 Ph Me H 5 85 159-161 EtOAc      -97.6 C.sub.15 H.sub.19 NO.sub.3 S.sub.2         (1.2, MeOH, 25) 10b      CH.sub.2 Ph Me H 5 74 amorph.  -151.0 C.sub.15 H.sub.19 NO.sub.3 S.sub.2              MeOH, 25)      *C.sub.12 H.sub.23 N is dicyclohexylamine.      **C.sub.4 H.sub.8 O.sub.2 is ethyl acetate.

    TABLE II       ##STR10##              Analysis (%)        Calcd.   Method of     (Found) Comp.  prepn.      Yield  Recrystn. [α].sub.D deg. .BHorizBrace. No. R.sup.6 R.sup.5      R.sup.2 n(Examp. No.) (%) mp. (°C.) solvent (c, solv., °C.)       Formula C H N        11 H H COPh 0 1 78 134-135.5 THFether +126.0 C.sub.19 H.sub.17      NO.sub.4 S.sub.258.90 4.42 3.61          (1.0, MeOH, 25)  (59.14) (4.38)      (3.56) 12 H H H 0 5 85 142-143.5 EtOAc +121.0 C.sub.12 H.sub.13 NO.sub.      3 S.sub.2 50.87 4.62 4.94          (1.2, MeOH, 25)  (51.11) (4.58)      (4.80) 13a H Me COPh 0 1 33 186-186.5 EtOAc +162.1 C.sub.20 H.sub.19      NO.sub.4 S.sub.2 59.83 4.77 3.49          (1.0, DMP, 25)  (59.77) (4.80)      (3.50) 13b H Me COPh 0 1 31 106-116 EtOAcc-hexane +104.9 C.sub.20      H.sub.19 NO.sub.4 S.sub.2 59.83 4.77 3.49          (1.0, DMF, 25)      (59.99) (4.75) (3.41) 14a H Me H 0 5 85 173-175 EtOAc +106.8 C.sub.13      H.sub.15 NO.sub.3 S.sub.2 52.51 5.08 4.71          (1.0, DMF, 25)      (52.77) (5.03) (4.65) 15 H H COPh 1 1 98 126-131 EtOAc +110.5 C.sub.20      H.sub.19 NO.sub.4 S.sub.2.H.sub.2 O 57.26 5.04 3.34          (1.0, MeOH,      25)  (57.21) (5.08) (3.36) 16 H H H 1 5 81 amorph.  +104.3 C.sub.13      H.sub.15 NO.sub.3 S.sub.2          (1.0, MeOH, 25) 17 H Me COPh 1 2 68      150-151.5 benzene-c-hexane +89.1 C.sub.21 H.sub.21 NO.sub.4 S.sub.2      60.70 5.09 3.37      4 58   (1.3, MeOH, 25)  (60.93) (5.01) (3.27) 18 H      Me H 1 5 54 oil  +72.2 C.sub.14 H.sub.17 NO.sub.3 S.sub.2          (0.5,      MeOH, 25) 19 4-Me H COPh 1 1 55 122-129 EtOAc +131.4 C.sub.21 H.sub.21      NO.sub.4 S.sub.2.H.sub.2 O 58.18 5.35 3.23          (1.0, MeOH, 26)      (58.20) (5.33) (3.28) 20 4-Me H H 1 5 74 amorph.  +125.2 C.sub.14      H.sub.17 NO.sub.3 S.sub.2 54.00 5.50 4.50          (1.0, MeOH, 26)      (53.81) (5.51) (4.28) 21 4-Me Me COPh 1 1 48 131-132 EtOAcn-hexane      +117.6 C.sub.22 H.sub.23 NO.sub.4 S.sub.2 61.52 5.40 3.26          (1.0,      MeOH, 26)  (61.60) (5.42) (3.26) 22 4-Me Me H 1 5 83 154-156 EtOAcc-hexan      e +112.9 C.sub.15 H.sub.19 NO.sub.3 S.sub.2 55.36 5.88 4.30      (1.0, MeOH, 25)  (55.23) (5.92) (4.22) 23 2-Cl H COPh 1 2 28 160-161      EtOAcc-hexane -58.2 C.sub.20 H.sub.18 ClNO.sub.4 S.sub.2          (1.0,      MeOH, 26) 24 2-Cl H H 1 5 86 133-134 EtOAc -64.6 C.sub.15 H.sub.14      ClNO.sub.3 S.sub.2          (1.0, MeOH, 26) 25 4-Cl H COPh 1 2 51      119-131 EtOAc +110.0 C.sub.20 H.sub.18 ClNO.sub.4 S.sub.2.H.sub.2 O      52.92 4.44 3.09          (1.0, MeOH, 26)  (52.84) (4.42) (3.09) 26 4-Cl      H H 1 5 90 amorph.  +77.1 C.sub.13 H.sub.14 ClNO.sub.3 S.sub.2      (1.0, MeOH, 26) 27 2,4-Cl.sub.2 H COPh 0 2 16 amorph.  -187.8 C.sub.19      H.sub.15 Cl.sub.2 NO.sub.4       S.sub.2          (1.0, MeOH, 26) 28 2,4-Cl.sub.2 H H 0 5 29 amorph.      -303.8 C.sub.12 H.sub.11 Cl.sub.2 NO.sub.3 S.sub.2          (0.3, MeOH,      25) 29a 4-F Me COPh 0 2 32 178-180 EtOAc +155.3 C.sub.20 H.sub.18      FNO.sub.4 S.sub.2          (1.0, MeOH, 26) 29b 4-F Me COPh 0 2 18      amorph.  +98.6 C.sub.20 H.sub.18 FNO.sub.4 S.sub.2          (1.1, MeOH,      26) 30a 4-F Me H 0 5 95 199-200 EtOAc +92.2 C.sub.13 H.sub.14 FNO.sub.32      S.sub.2 49.51 4.47 4.44          (1.0, MeOH, 26)  (49.56) (4.43) (4.47)      31 2-NO.sub.2 Me COPh 1 2 69 amorph. MeOH -257.0 C.sub.21 H.sub.20      N.sub.2 O.sub.6 S.sub.2 61.75 6.75 6.55        225-226  (0.4, MeOH, 25)      C.sub.21 H.sub.20 N.sub.2 O.sub.6 S.sub. 2.C.sub.12 H.sub.25 N* (61.42)      (6.69) (6.41)          -158.0          (1.0, MeOH, 25) 32 2-NO.sub.2 Me      H 1 5 65 118-121 EtOAcbenzene -284.7 C.sub.14 H.sub.16 N.sub.2 O.sub.5      S.sub.2.1/2 C.sub.6 H.sub.6 51.63 4.84 7.08          (0.4, MeOH, 26)      (51.47) (4.77) (7.00) 33 3-NO.sub.2 Me COPh 1 2 43 128-130 benzene +34.0      C.sub.21 H.sub.20 N.sub.2 O.sub.6 S.sub.2          (1.0, MeOH, 25) 34      3-NO.sub.2 Me H 1 5 55 153-154 EtOAc +94.9 C.sub.14 H.sub.16 N.sub.2      O.sub.3 S.sub.2 47.18 4.52 7.86          (1.0, MeOH, 25)  (46.82) (4.46)      (7.52) 35 4-NO.sub.2 Me COPh 1 2 60 oil MeOH -234.0 C.sub.21 H.sub.20      N.sub.2 O.sub.6 S.sub.2        223-228  (0.6, MeOH, 26) C.sub.21      H.sub.20 N.sub.2 O.sub. 6 S.sub.2.C.sub.12 H.sub.25 N* 36 4-NMe.sub.2 Me      COPh 1 1 90 138-142   C.sub.23 H.sub.26 N.sub.2 O.sub.4 S.sub.2      dec. 37 4-NMe.sub.2 Me H 1 5 65 amorph.  +4.2 C.sub.16 H.sub.22 N.sub.2      O.sub.5 S.sub.2          (0.5, MeOH, 25) 38 4-NHAc Me COPh 1 2 87 oil      +121.6 C.sub.23 H.sub.24 N.sub.2 O.sub.5 S.sub.2          (0.9, MeOH,      25) 39 4-NHAc Me H 1 5 25 169-173 EtOAc +126.0 C.sub.16 H.sub.20 N.sub.      2 O.sub.4 S.sub.2          (1.1, MeOH, 25) 40 4-NHCO.sub.2 CH.sub.2 Ph      Me COPh 1 2 53 oil  +114.3 C.sub.29 H.sub.28 N.sub.2 O.sub.6 S.sub.2           (0.5, MeOH, 25) 41 2-CO.sub.2 H H COPh 1 1 72 115-120 EtOAcbenzene      +171.8 C.sub.21 H.sub.19 NO.sub.6 S.sub.2 .3/4 C.sub. 6 H.sub.6 60.6      4.70 2.78          (1.0, MeOH, 25)  (60.87) (4.74) (2.80) 42 2-CO.sub.2      H H H 1 5 81 207-208 EtOAcMeOH +236.5 C.sub.14 H.sub.15 NO.sub.5 S.sub.2      49.25 4.43 4.10        dec.  (0.6, MeOH, 25)  (49.41) (4.45) (4.13) 43      2-OH H COPh 0 2 46 amorph.  +126.9 C.sub.19 H.sub.17 NO.sub.5 S.sub.2            (1.0, MeOH, 26) 44 2-OH H H 0 5 67 156-158 EtOAcMeOH +193.4      C.sub.12 H.sub.15 NO.sub.4 S.sub.2 48.15 4.38 4.68        dec.  (1.0,      MeOH, 26)  (47.75) (4.19) (4.53) 45 2-OH H COPh 1 2 58 100.5-101      EtOAcbenzene +130.8 C.sub.20 H.sub.19 NO.sub.5 S.sub.2.C.sub.6 H.sub.6      63.01 5.08 2.83        dec.  (1.0, MeOH, 26)  (63.01) (5.07) (2.61) 46      2-OH H H 1 5 70 146-148 EtOAc +176.0 C.sub.13 H.sub.15 NO.sub. 4 S.sub.2      49.82 4.82 4.47          (1.0, MeOH, 26)  (49.74) (4.88) (4.32) 47 2-OH      H COPh 2 2 48 111-113 EtOAcc-hexane +112.1 C.sub.21 H.sub.21 NO.sub.5      S.sub.2.3/4 C.sub.6 H.sub.12 ** 61.92 6.11 2.83        dec.  (1.0, MeOH,      26)  (62.15) (6.08) (2.59) 48 2-OH H H 2 5 62 amorph.  +138.4 C.sub.14      H.sub.17 NO.sub.4 S.sub.2          (1.0, MeOH, 26) 49 2-OH Me COPh 1 2      76 amorph.  +118.1 C.sub.21 H.sub.21 NO.sub.5 S.sub.2          (1.0,      MeOH, 26) 50 2-OH Me H 1 5 84 167-168 EtOAc +160.6 C.sub.14 H.sub.17      NO.sub.4 S.sub.2        dec.  (1.0, MeOH, 26) 51 3-OCOPh H COPh 1 2 52      amorph.  +85.1 C.sub.26 H.sub.23 NO.sub.6 S.sub.2          (1.0, MeOH,      27) 52 3-OH H H 1 5 69 156-157 EtOAcMeOH +122.4 C.sub.13 H.sub.15      NO.sub.4 S.sub.2 49.82 4.82 4.47         c-hexane (1.0, MeOH, 26)      (49.66) (4.72) (4.35) 53 3-OCOPh Me COPh 1 2 66 131.5-132 acetone +86.1      C.sub.27 H.sub.25 NO.sub.6 S.sub.2 61.93 4.81 2.67        dec.  (1.0,      MeOH, 26)  (62.32) (4.45) (2.60) 54 3-OH Me H 1 5 62 amorph.  +73.2      C.sub.14 H.sub.17 NO.sub.4       S.sub.2          (1.0, MeOH, 26) 55 4-OCO.sub.2 CH.sub.2 Ph H COPh 1 1      69 101-104 EtOAc +98.3 C.sub.27 H.sub.25 NO.sub.7 S.sub.2          (1.0,      MeOH, 26) 56 4-OH H H 1 5 67 amorph.  +78.5 C.sub.13 H.sub.15 NO.sub.4      S.sub.2          (1.0, MeOH, 26) 57 3,4-(OH).sub.2 H COPh 1 1 67 amorph.       +117.6 C.sub.20 H.sub.19 NO.sub.6 S.sub.2          (1.0, MeOH, 27) 58      3,4-(OH).sub.2 H H 1 5 82 amorph.  +104.5 C.sub.13 H.sub.15 NO.sub.5      S.sub.2          (1.0, MeOH, 27) 59 2-OH, 5-Cl Me COPh 1 2 60 amorph.      +108.2 C.sub.21 H.sub.20 ClNO.sub.5 S.sub.2          (1.0, MeOH, 25) 60      2-OH, 5-Cl Me H 1 5 62 159-160 EtOAcbenzene +170.7 C.sub.14 H.sub.16      ClNO.sub.4 S.sub.2.2/5 C.sub.6 H.sub.6 50.11 4.72 3.56        dec.      (1.0, MeOH, 25)  (50.09) (4.69) (3.35) 61 2-OMe H COPh 1 2 63 85-89      EtOAc +139.5 C.sub.21 H.sub.21 NO.sub.5 S.sub.2 58.45 4.90 3.25      (1.1, MeOH, 25)  (58.24) (5.21) (2.96) 62 2-OMe H H 1 5 73 138-139 EtOAc      +186.6 C.sub.14 H.sub.17 NO.sub.4 S.sub.2 51.36 5.23 4.28          (1.0,      MeOH, 25)  (51.02) (5.16) (4.22) 63 2-OMe Me COPh 1 2 72 169- 170 EtOAc      +130.0 C.sub.22 H.sub.23 NO.sub.5 S.sub.2 59.31 5.20 3.14          (1.1,      MeOH, 25)  (59.26) (5.18) (3.16) 64 2-OMe Me H 1 5 41 145-146 EtOAc      +173.8 C.sub.15 H.sub.19 NO.sub.4 S.sub.2 52.77 5.61 4.10          (1.1,      MeOH, 25)  (52.51) (5.59) (4.12) 65 4-OMe H COPh 1 2 88 114-116 EtOAc      +128.3 C.sub.21 H.sub.21 NO.sub.5 S.sub.2.3/2 H.sub.2 O 55.01 5.28 3.05              (1.0, MeOH, 26)  (55.21) (4.98) (3.04) 66 4-OMe H H 1 5 88 oil      +92.3 C.sub.14 H.sub.17 NO.sub.4 S.sub..sub.2          (0.9, MeOH, 25)      67 4-OMe Me COPh 1 2 81 oil acetone-ether +109.8 C.sub.22 H.sub.23      NO.sub.5 S.sub.2        168-170  (0.8, MeOH, 25) C.sub.22 H.sub.23      NO.sub.5 S.sub.2.C.sub.12 H.sub.23 N*          +85.6          (1.1,      MeOH, 25) 68 4-OMe Me H 1 5 85 139-140 EtOAc +120.3 C.sub.15 H.sub.19      NO.sub.4 S.sub.2 52.77 5.61 4.10          (1.0, MeOH, 25)  (52.44)      (5.51) (4.03) 69 3,4-(OMe).sub.2 H COPh 1 2 55 oil  +154.0 C.sub.22      H.sub.23 NO.sub.6 S.sub.2          (1.0, MeOH, 25) 70 3,4,5-(OMe).sub.3      Me COPh 1 2 89 amorph.  +130.5 C.sub.24 H.sub.27 NO.sub.7 S.sub.2        (1.0, MeOH, 24) 71 3,4,5-(OMe).sub.3 Me H 1 5 31 amorph.  +115.0      C.sub.17 H.sub.23 NO.sub.6 S.sub.2          (1.5, MeOH, 24) 72 2-OH,      3-OMe H COPh 1 2 55 135-137 benzene +132.2 C.sub.21 H.sub.21 NO.sub.6      S.sub.2.1/5 C.sub.6 H.sub.6 57.57 4.83 3.02          (1.0, MeOH, 28)      (57.36) (4.81) (2.82) 73 2-OH, 3-OMe H H 1 5 78 amorph.  +144.5 C.sub.14      H.sub.17 NO.sub.5 S.sub.2          (1.0, MeOH, 28) 74 2-OH, 4-OMe H COPh      1 2 72 amorph.  +54.6 C.sub.21 H.sub.21 NO.sub.6 S.sub.2          (1.1,      MeOH, 24) 75 2-OH, 4-OMe H H 1 5 82 134-135 acetone-benzene +179.0      C.sub.14 H.sub.17 NO.sub.5 S.sub.2          (1.1, MeOH, 24) 76 2-OH,      4-OMe Me COPh 1 2 82 152 benzene-ether +163.2 C.sub.22 H.sub.23 NO.sub.6      S.sub.2        dec.  (0.9, MeOH, 25) 77 2-OH, 4-OMe Me H 1 5 68 147-148      EtOAc +146.2 C.sub.15 H.sub.19 NO.sub.5 S.sub.2 50.40 5.36 3.92      (1.0, MeOH, 24)  (50.68) (5.69) (3.53) 78 4-OH, 3-OMe Me COPh 1 2 63      amorph.  +96.0 C.sub.27 H.sub.31 NO.sub.7 S.sub.2          (1.1, MeOH,      26) 79 4-OH, 3-OMe Me H 1 5 62 amorph.  +104.7 C.sub.15 H.sub.19      NO.sub.5 S.sub.2          (1.0, MeOH, 26) 80 3,4-OCH.sub.2 O Me COPh 1 2      98 amorph.  +98.8 C.sub.22 H.sub.21 NO.sub.6 S.sub.2          (1.0,      MeOH, 25) 81 3,4-OCH.sub.2 O Me H 1 5 82 amorph.  +105.2 C.sub.15      H.sub.17 NO.sub.5      *C.sub.12 H.sub.23 N is dicyclohexylamine.      **C.sub.6 H.sub.12 is cyclohexane.

                                      TABLE III                                    __________________________________________________________________________      ##STR11##                                                                                       Method                           Analysis (%)                                  of                 [α].sub.D                                                                              Calcd.                                        prepn.             deg.          (Found)                     Compd.            (Examp.                                                                             Yield    Recrystn.                                                                           (c,           .BHorizBrace.               No.  R.sup.1                                                                              R.sup.5                                                                           R.sup.2                                                                            No.) (%) (°C.)                                                                        solvent                                                                             solv., °C.)                                                                   Formula  C   H   N                  __________________________________________________________________________     82                                                                                   ##STR12##                                                                           Me COPh                                                                               2    75  amorph.   -101.0(1.5,MeOH, 26)                                                                 C.sub.25 H.sub.23 NO.sub.4                                                     S.sub.2                             83                                                                                   ##STR13##                                                                           Me H   5    69  amorph.   -202.0(0.6,MeOH, 26)                                                                 C.sub.18 H.sub.19 NO.sub.3                                                     S.sub.2                             84                                                                                   ##STR14##                                                                           Me COPh                                                                               2    82  122-123                                                                             benzene-n-hexane                                                                    +45.5(1.0,MeOH, 25)                                                                  C.sub.19 H.sub.19 NO.sub.5                                                     S.sub.2 56.28(56.39)                                                                       4.72(4.57)                                                                         3.45(3.36)          85                                                                                   ##STR15##                                                                           Me H   5    85  oil       +48.8(1.0,MeOH, 25)                                                                  C.sub.12 H.sub.15 NO.sub.4                                                     S.sub.2                             86                                                                                   ##STR16##                                                                           Me COPh                                                                               1    81  125-126                                                                             benzene-n-hexane                                                                    +79.9(1.0,MeOH, 25)                                                                  C.sub.20 H.sub.21 NO.sub.5                                                     S.sub.2 57.26(57.62)                                                                       5.05(5.04)                                                                         3.34(3.30)          87                                                                                   ##STR17##                                                                           Me H   5    79  oil       +78.1(1.0,MeOH, 25)                                                                  C.sub.13 H.sub.17 NO.sub.4                                                     S.sub.2                             88                                                                                   ##STR18##                                                                           H  COPh                                                                               3    57  141-143                                                                             benzene                                                                             +107.7(1.0,MeOH, 25)                                                                 C.sub.18 H.sub.17 NO.sub.4                                                     S.sub.3 53.05(52.93)                                                                       4.20(4.01)                                                                         3.44(3.31)          89                                                                                   ##STR19##                                                                           H  H   5    56  amorph.   +87.5(1.0,MeOH, 25)                                                                  C.sub.11 H.sub.13 NO.sub.3                                                     S.sub.3                             90                                                                                   ##STR20##                                                                           Me COPh                                                                               4    49  136-137                                                                             benzene                                                                             +79.6(1.0,MeOH, 25)                                                                  C.sub.19 H.sub.19 NO.sub.4                                                     S.sub.3 54.14(56.19)                                                                       4.54(4.36)                                                                         3.32(3.26)          91                                                                                   ##STR21##                                                                           Me H   5    42  amorph.   +55.7(1.0,MeOH, 26)                                                                  C.sub.12 H.sub.15 NO.sub.5                                                     S.sub.3                             92                                                                                   ##STR22##                                                                           Me COPh                                                                               2    79  amorph.   +59.0(1.0,MeOH, 25)                                                                  C.sub.20 H.sub.20 N.sub.2                                                      O.sub.4 S.sub.2                                                                        57.67(57.29)                                                                       4.84(5.49)                                                                         6.73(6.46)          93                                                                                   ##STR23##                                                                           Me H   5    83  amorph.   -13.5(1.0,MeOH, 25)                                                                  C.sub.13 H.sub.16 N.sub.2                                                      O.sub.3 S.sub.2                     94                                                                                   ##STR24##                                                                           Me COPh                                                                               2    60  amorph.   -4.4(1.1,MeOH, 25)                                                                   C.sub.20 H.sub.20 N.sub.2                                                      O.sub.4 S.sub.2                     95                                                                                   ##STR25##                                                                           Me H   5    61  amorph.   +64.0(1.0,MeOH, 23)                                                                  C.sub.13 H.sub.16 N.sub.2                                                      O.sub.3 S.sub.2                     __________________________________________________________________________

The potent antihypertensive effect of the compounds of foumula I and salts thereof is clear in comparison with that of certain antihypertensive compound as explained below. The inhibitor of angiotensin I-converting enzyme which converts biologically inactive decapeptide, angiotensin I, to active octapeptide, angiotensin II, is found useful as antihypertensive medicine [R. L. Soffer, Annual Review of Biochemistry, 45, 73 (1976); M. A. Ondetti et al., Science, 196, 441 (1977)]. In view of the above, we investigated the pharmacological activities of the compounds of this invention from the aspect of inhibitory activity against the enzyme.

PHARMACOLOGICAL TEST 1

As the method of measurement of angiotensin I-converting enzyme activity, bioassay for the contractile response of isolated smooth muscle or the pressor response of normal animals and biochemical assay for the enzyme isolated from lung or other organs of animals are known. The former is found more advantageous than the latter for the examination of the conversion of angiotensin I to angiotensin II in vivo.

In the present study, therefore, we adopted the bioassay for contractile response of isolated guinea pig ileum to angiotensin I.

Measurement of inhibitory activity of angiotensin I-converting enzyme

Isolated guinea pig ileum was suspended in the organ bath containing 20 ml of Tyrode's solution of 30° C. gassed with 95% O₂ +5% CO₂. The contraction induced by the addition of angiotensin I (0.1 μg/ml) at intervals of 10 minutes was recorded on a recticorder (Nihon Koden) for 90 seconds using FD pick up (ST-1T-H, Nihon Koden).

The test compounds were added to the bath 5 minutes before the addition of angiotensin I.

The inhibitory activity of angiotensin I-converting enzyme was calculated by the following formula. ##EQU1##

A: contractile intensity of angiotensin I before addition of the compound,

B: contractile intensity of angiotensin I after addition of the compound.

From the fact that kininase II, which destroys bradykinin having contractive action on isolated guinea pig ileum, is thought to be identical with angiotensin I-converting enzyme, augmentation of the contractile response to bradykinin by test compounds was examined by using bradykinin (0.005 μg/ml) in place of angiotensin I according to the above mentioned method.

The results are shown in Table IV. All of the test compounds inhibited the contractile response to angiotensin I, while they enhanced the response to bradykinin.

PHARMACOLOGICAL TEST 2

The activity of angiotensin I-converting enzyme was measured by spectrophotometry according to the method of D. W. Cushman and H. S. Cheung [Biochem. Pharmacol., 20, 1637 (1971)]. That is, the absorbance of hippuric acid was measured, which is liberated by incubating hippuryl-L-histidyl-L-leucine (HHL) as substrate in the presence of angiotensin I-converting enzyme extracted from rabbit lung.

Measurement of inhibitory activity of angiotensin I-converting enzyme

The reaction mixture is as follows:

100 mM phosphate buffer (pH 8.3)

300 mM sodium chloride

5 mM HHL

10⁻³ ˜10⁻⁹ M enzyme inhibitor

5 mU enzyme

0.25 ml of the above mixture was incubated at 37° C. for 30 minutes and the reaction was stopped by adding 0.25 ml of 1 N hydrochloric acid. To this solution, 1.5 ml of ethyl acetate was added in order to extract hippuric acid. 1.0 ml of ethyl acetate layer was collected and evaporated to dryness, and the residue obtained was dissolved in 1.0 ml of water. The absorbance of this solution was measured at 228 nm.

The inhibitory activity of angiotensin I-converting enzyme was calculated by the following formula: ##EQU2##

A: absorbance of reaction solution before addition of the compound,

B: absorbance of reaction solution after addition of the compound.

Concentration of compound producing 50% inhibition of angiotensin I-converting enzyme (IC₅₀)

The solution containing compounds at the concentration of 1×10⁻³ M to 1×10⁻⁹ M was incubated and percent inhibition at each concentration was calculated according to the above formula, and then IC₅₀, concentration of the compound producing 50% inhibition of the enzyme activity, was determined.

The results are shown in Table IV.

PHARMACOLOGICAL TEST 3

Male Wistar strain rats weighing about 200-300 g were used.

Under ether anesthesia, polyethylene cannulae are inserted into carotid artery and jugular vein. The cannula to carotid artery is connected to an electric transducer, while the cannula to jugular vein is connected to an apparatus for continuous infusion. After the complete recovery from anesthesia, angiotensin I is infused intravenously in a dose of 300 ng/kg by the apparatus for continuous infusion, and the pressor response is recorded by polygraph (Nihon Koden, RM-150).

The compounds of this invention suspended in 0.5% tragacanth solution are administered orally in a dose of 0.3 ml per 100 g of body weight, and the pressor response to angiotensin I infused intravenously is measured with time.

The inhibitory activity of the compounds against angiotensin I-converting enzyme is expressed as the percent inhibition of pressor response to angiotensin I.

Table V shows the changes of percent inhibition of the compounds of this invention with time.

TOXICITY TEST

Acute toxicity of the compounds of this invention is shown in Table IV.

(Experimental animals)

The male ddy-SLC strain rats (4 weeks of age, weighing 19-21 g) were placed in a breeding room of constant temperature and humidity (23±1° C., 55±5%) and fed freely pellet diet (CE-2, Clea Japan Inc.) and water ad. libitum for a week. The rats showing the normal growth were selected for the experiment.

(Method of administration)

Test compounds are suspended in 0.5% tragacanth solution (p.o.) or dissolved in distilled water (i.v., i.p.), and administered in a dose of 0.5 ml/20 body weight.

                  TABLE IV                                                         ______________________________________                                         Inhibitory activity of the compounds against angiotensin I-                    converting enzyme                                                                                 Angiotensin                                                 Compound                                                                               Angiotensin I                                                                             I-converting enzyme                                                                           Bradykinin                                   No.     IC.sub.50 * [M]                                                                           IC.sub.50 ** [M]                                                                              AC.sub.50 *** [M]                            ______________________________________                                         2       4.8 × 10.sup.-7                                                                     3.2 × 10.sup.-6                                                                         1.9 × 10.sup.-8                        4       5.0 × 10.sup.-8                                                                     1.2 × 10.sup.-7                                                                         2.0 × 10.sup.-9                        6a      4.1 × 10.sup.-7                                                                     6.5 × 10.sup.-7                                                                         1.5 × 10.sup.-8                        6b      3.0 × 10.sup.-7                                                                     3.7 × 10.sup.-7                                                                         3.7 × 10.sup.-9                        8a      8.5 × 10.sup.-8                                                                     2.5 × 10.sup.-7                                                                         1.4 × 10.sup.-9                        8b      1.4 × 10.sup.-7                                                                     2.9 × 10.sup.-7                                                                         1.1 × 10.sup.-9                         10a    8.1 × 10.sup.-7                                                                     2.8 × 10.sup.-6                                                                         1.3 × 10.sup.-8                         10b    5.8 × 10.sup.-7                                                                     3.1 ×  10.sup.-7                                                                        1.0 × 10.sup.-8                        12      9.0 × 10.sup.-7                                                                     1.3 × 10.sup.-5                                                                         1.9 × 10.sup.-8                        16      2.4 × 10.sup.-7                                                                     4.5 × 10.sup.-7                                                                         2.6 × 10.sup.-9                        18      1.9 × 10.sup.-7                                                                     6.0 × 10.sup.-8                                                                         3.1 × 10.sup.-9                        22      1.7 × 10.sup.-7                                                                     5.4 × 10.sup.-7                                                                         3.9 × 10.sup.-9                        24      7.0 × 10.sup.-7                                                                     3.6 × 10.sup.-6                                                                         1.6 × 10.sup.-8                        34      1.8 × 10.sup.-7                                                                     4.0 × 10.sup.-7                                                                         2.5 × 10.sup.-9                        44      5.6 × 10.sup.-7                                                                     2.2 × 10.sup.-6                                                                         5.0 × 10.sup.-9                        46      1.9 × 10.sup.-8                                                                     7.0 × 10.sup.-8                                                                         .sup. 3.0 × 10.sup.-10                 50      5.6 × 10.sup.-8                                                                     2.2 × 10.sup.-7                                                                         .sup. 7.0 × 10.sup.-10                 52      7.1 × 10.sup.-8                                                                     2.1 × 10.sup.-7                                                                         1.5 × 10.sup.-9                        54      1.5 × 10.sup.-7                                                                     2.3 × 10.sup.-7                                                                         1.7 × 10.sup.-9                        56      4.6 × 10.sup.-7                                                                     1.2 × 10.sup.-6                                                                         5.5 × 10.sup.-9                        58      5.2 × 10.sup.-7                                                                     2.6 × 10.sup.-6                                                                         5.8 × 10.sup.-9                        60      9.2 × 10.sup.-8                                                                     7.5 × 10.sup.-8                                                                         2.0 × 10.sup.-9                        64      5.0 × 10.sup.-7                                                                     4.2 × 10.sup.-7                                                                         8.0 × 10.sup.-9                        68      8.8 × 10.sup.-8                                                                     7.5 × 10.sup.-7                                                                         2.1 × 10.sup.-9                        71      4.1 × 10.sup.-7                                                                     3.9 × 10.sup.-7                                                                         9.4 × 10.sup.-9                        73      3.6 × 10.sup.-8                                                                     9.3 × 10.sup.-8                                                                         1.1 × 10.sup.-9                        75      1.4 × 10.sup.-7                                                                     2.0 × 10.sup.-7                                                                         3.1 × 10.sup.-9                        77      1.2 × 10.sup.-7                                                                     1.9 × 10.sup.-7                                                                         1.3 × 10.sup.-9                        79      2.1 × 10.sup. -7                                                                    1.3 × 10.sup.-6                                                                         3.2 × 10.sup.-9                        81      1.4 × 10.sup.-7                                                                     2.4 × 10.sup.-7                                                                         .sup. 9.4 × 10.sup.-10                 83      3.6 × 10.sup.-7                                                                     1.3 × 10.sup.-6                                                                         1.3 × 10.sup.-8                        85      2.4 × 10.sup.-7                                                                     3.4 × 10.sup.-7                                                                         3.7 × 10.sup.-9                        87      4.6 × 10.sup.-7                                                                     7.3 × 10.sup.-7                                                                         2.6 × 10.sup.-9                        91      7.0 × 10.sup.-7                                                                     3.7 × 10.sup.-7                                                                         1.0 × 10.sup.-8                        93      1.4 × 10.sup.-7                                                                     8.4 × 10.sup.-7                                                                         2.9 × 10.sup.-9                        95      8.3 × 10.sup.-8                                                                     1.1 × 10.sup.-7                                                                         3.1 × 10.sup.-9                          96****                                                                               1.7 × 10.sup.-7                                                                     2.6 × 10.sup.-7                                                                         2.6 × 10.sup.-9                        ______________________________________                                          *Concentration of compound producing 50% inhibition of angiotensin I           activity inducing the contraction of guinea pig ileum.                         **Concentration of compound producing 50% inhibition of angiotensin I          converting enzyme.                                                             ***Concentration of compound producing 50% augmentation of bradykinin          activity inducing the contraction of guinea pig ileum.                         ****(4R)3-[(2S)3-Mercapto-2-methylpropanoyl4-thiazolidinecarboxylic acid.

                                      TABLE V                                      __________________________________________________________________________               Inhibition (%)                                                       Compd.                                                                              Dose (min.)                                                               No.  (mg/kg)                                                                             5  15 25 35 45 55 65 75 85 95 105                                                                               115                                 __________________________________________________________________________      3   1.8  35.2                                                                              40.8                                                                              26.9                                                                              17.9                                                                              14.2                                                                              14.8                                                                               6.3                                                                               9.5                                                                               5.8                                          4   1.3  46.7                                                                              46.5                                                                              37.2                                                                              32.2                                                                              28.8                                                                              27.5                                                                              27.5                                                                              13.8                                                                              14.5                                                                              10.3                                       45* 1.8  20.0                                                                              26.6                                                                              30.1                                                                              31.8                                                                              20.9                                                                              13.5                                                                              19.0                                                                              14.9                                                                              20.9                                                                              10.3                                                                              10.3                                                                               8.8                                46   1.3  53.3                                                                              62.9                                                                              64.7                                                                              63.7                                                                              54.0                                                                              49.3                                                                              47.7                                                                              38.8                                                                              34.0                                                                              30.0                                                                              30.0                                                                              31.0                                49   1.8  27.8                                                                              34.4                                                                              42.9                                                                              38.5                                                                              47.7                                                                              43.7                                                                              47.0                                                                              45.6                                                                              31.6                                                                              31.7                                                                              30.4                                                                              35.0                                50   1.4  11.1                                                                              22.7                                                                              37.6                                                                              43.9                                                                              52.6                                                                              31.7                                                                              28.1                                                                              30.5                                                                              24.3                                                                              21.1                                                                              21.7                                                                              21.5                                76   2.0  26.0                                                                              45.9                                                                              56.1                                                                              55.9                                                                              58.2                                                                              47.1                                                                              48.9                                                                              40.7                                                                              41.7                                                                              32.2                                                                              30.6                                                                              28.5                                77   1.5  35.0                                                                              45.0                                                                              54.2                                                                              50.8                                                                              57.2                                                                              49.2                                                                              47.8                                                                              34.8                                                                              31.7                                                                              24.2                                                                              18.7                                                                               6.7                                __________________________________________________________________________      *solvent free                                                            

                  TABLE VI                                                         ______________________________________                                         Compound                                                                       No.     p.o.        i.v.         i.p.                                          ______________________________________                                         18                               LD >                                                                           1000 mg/kg*                                   46      LD.sub.50 > LD.sub.50 >                                                        10000 mg/kg 1100-1300 mg/kg*                                           ______________________________________                                          *pH 7                                                                    

It is found from the above pharmacological tests that the compounds I of this invention are useful as antihypertensive agents. The compounds can be given with the combination of diuretics such as hydroflumethiazide, furosemide, and bumetanide same as other antihypertensive agents. The compounds can be administered either orally or parenterally. The dosage forms are tablet, capsule, granule, powder, suppository, injection, etc. In the treatment of hypertention, these preparations can contain not only general excipients but also other antihypertensive agents such as reserpine, α-methyldopa, guanethidine, clonidine, hydralazine, etc. The dose is adjusted depending on symptom, dosage form, etc. But, usual daily dosage is 1 to 5000 mg, preferably 10 to 100 mg, in one or a few divided doses.

EXAMPLES OF FORMULATION (1) Oral drug

    ______________________________________                                         a.     tablet                                                                         compound 46            30 mg                                                   lactose                150 mg                                                  crystalline cellulose  50 mg                                                   calcium carboxymethylcellulose                                                                        7 mg                                                    magnesium stearate     3 mg                                                    Total                  240 mg                                           -      compound 46            150 mg                                                  lactose                60 mg                                                   crystalline cellulose  30 mg                                                   calcium carboxymethylcellulose                                                                        7 mg                                                    magnesium stearate     3 mg                                                    Total                  250 mg                                           -      compound 49            50 mg                                                   lactose                120 mg                                                  crystalline cellulose  60 mg                                                   calcium carboxymethylcellulose                                                                        7 mg                                                    magnesium stearate     3 mg                                                    Total                  240 mg                                           -      compound 81            100 mg                                                  lactose                95 mg                                                   crystalline cellulose  45 mg                                                   calcium carboxymethylcellulose                                                                        7 mg                                                    magnesium stearate     3 mg                                                    Total                  250 mg                                           ______________________________________                                    

The tablets may be treated with the common film-coating and further with sugar-coating.

    ______________________________________                                         b.     granule                                                                        compound 46         30 mg                                                      polyvinylpyrrolidone                                                                               25 mg                                                      lactose             385 mg                                                     hydroxypropylcellulose                                                                             50 mg                                                      talc                10 mg                                                      Total               500 mg                                              -      compound 73         150 mg                                                     polyvinylpyrrolidone                                                                               20 mg                                                      lactose             280 mg                                                     hydroxypropylcellulose                                                                             40 mg                                                      talc                10 mg                                                      Total               500 mg                                              -c.    powder                                                                         compound 46         30 mg                                                      lactose             500 mg                                                     starch              440 mg                                                     colloidal silica    30 mg                                                      Total               1000 mg                                             -      compound 46         300 mg                                                     lactose             230 mg                                                     starch              440 mg                                                     colloidal silica    30 mg                                                      Total               1000 mg                                             -      compound 95         250 mg                                                     lactose             240 mg                                                     starch              480 mg                                                     colloidal silica    30 mg                                                      Total               1000 mg                                             -d.    capsule                                                                        compound 46         30 mg                                                      lactose             102 mg                                                     crystalline cellulose                                                                              56 mg                                                      colloidal silica    2 mg                                                       Total               190 mg                                              -      compound 50         100 mg                                                     lactose             60 mg                                                      crystalline cellulose                                                                              38 mg                                                      colloidal silica    2 mg                                                       Total               200 mg                                              -      compound 22         200 mg                                                     glycerol            179.98 mg                                                  butyl p-hydroxybenzoate                                                                            0.02 mg                                                    Total               380 mg                                              -      compound 46         30 mg                                                      glycerol            349.98 mg                                                  butyl p-hydroxybenzoate                                                                            0.02 mg                                                    Total               380 mg                                              ______________________________________                                    

(2) Injection

a. 1 to 30 mg of compound 46 is contained in 1 ml of the aqueous solution (pH 6.5-7.0). 

What we claim is:
 1. A compound of the formula ##STR26## wherein R¹ is phenyl substituted by at least one substituent selected from the group consisting of lower alkylenedioxy, amino, lower alkylamino, lower alkanoylamino, benzoylamino, and benzyloxycarbonylamino, wherein the terms lower alkyl, lower alkanoyl and lower alkylene refer to groups having from 1 to 4 carbon atoms;R² is hydrogen or benzoyl; A is straight or branched alkylene with 1 to 3 carbon atoms; and pharmaceutically acceptable salts thereof.
 2. A compound of the formula ##STR27## wherein R¹ is phenyl substituted by at least one substituent selected from the group consisting of lower alkoxy and halogen, said phenyl nucleus is also substituted by at least one substituent selected from the group consisting of hydroxy and lower alkanoyloxy, wherein the terms lower alkoxy and lower alkanoyl refer to groups having 1 to 4 carbon atoms;R² is hydrogen or benzoyl; A is straight or branched alkylene with 1 to 3 carbon atoms;and pharmaceutically acceptable salts thereof.
 3. A compound of the formula ##STR28## wherein R¹ is phenyl and phenyl substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, halogen and nitro, wherein the terms lower alkyl and lower alkoxy refer to groups having 1 to 4 carbon atoms;R² is hydrogen or benzoyl; A is straight or branched alkylene with 1 to 3 carbon atoms and pharmaceutically acceptable salts thereof.
 4. A compound of the formula ##STR29## wherein R¹ is phenyl substituted by carboxy;R² is hydrogen or benzoyl; A is straight or branched alkylene of 1 to 3 carbon atoms; and pharmaceutically acceptable salts thereof.
 5. A compound of the formula ##STR30## wherein R¹ is naphthyl or naphthyl substituted by at least one substituent selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, halogen, nitro, amino, lower alkylamino, lower alkanoylamino, and benzoylamino, wherein the terms lower alkyl, lower alkoxy, lower alkylene and lower alkanoyl refer to groups having 1 to 4 carbon atoms;R² is hydrogen or benzoyl; A is straight or branched alkylene with 1 to 3 carbon atoms;and pharmaceutically acceptable salts thereof.
 6. A compound as in claim 1 wherein R¹ is 4-dimethylaminophenyl, 4-acetaminophenyl, 4-benzyloxycarbonylaminophenyl, or 3,4-methylenedioxyphenyl.
 7. A compound as in claim 2 wherein R¹ is 5-chloro-2-hydroxyphenyl, 2-hydroxy-3-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, or 3-methoxy-4-pivaloyloxyphenyl.
 8. A compound as in claim 3 wherein R¹ is phenyl, 4-methylphenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-fluorophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl or 3,4,5-trimethoxyphenyl.
 9. A compound as in claim 1 wherein A is --CH₂ --, --CH(CH₃)--, --CH₂ CH₂ -- or --CH(CH₃)CH₂ --.
 10. A compound as in claim 2 wherein A is --CH₂ --, --CH(CH₃)--, --CH₂ CH₂ -- or --CH(CH₃)CH₂ --.
 11. A compound as in claim 3 wherein A is --CH₂ --, --CH(CH₃)--, --C(CH₃)₂ --, --CH(C₂ H₅)-- or --CH₂ CH₂ CH₂ --.
 12. A compound as in claim 4 wherein A is --CH₂ --, --CH(CH₃)--, --CH₂ CH₂ -- or --CH(CH₃)CH₂ --.
 13. A compound as in claim 5 wherein A is --CH₂ --, --CH(CH₃)--, --CH₂ CH₂ -- or --CH(CH₃)CH₂ --.
 14. (2R, 4R)-3-Mercaptoacetyl-2-phenyl-4-thiazolidinecarboxylic acid of the formula of claim
 3. 15. (4R)-2-(4-Dimethylaminophenyl)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid of the formula of claim
 1. 16. (4R)-2-(4-Acetaminophenyl)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid of the formula of claim
 1. 17. (4R)-2-(2-Carboxyphenyl)-3-(3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid of the formula of claim
 4. 18. (4R)-3-[(2S)-S-Benzoyl-3-mercapto-2-methylpropanoyl]-2-(5-chloro-2-hydroxyphenyl)-4-thiazolidinecarboxylic acid of the formula of claim
 2. 19. (4R)-2-(5-Chloro-2-hydroxyphenyl)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid of the formula of claim
 2. 20. (4R)-3-(S-Benzoyl-3-mercaptopropanoyl)-2-(2-hydroxy-3-methoxyphenyl)-4-thiazolidinecarboxylic acid of the formula of claim
 2. 21. (4R)-2-(2-Hydroxy-3-methoxyphenyl)-3-(3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid of the formula of claim
 2. 22. (4R)-2-(4-Hydroxy-3-methoxyphenyl)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid of the formula of claim
 2. 23. (4R)-3-[(2S)-3-Mercapto-2-methylpropanoyl]-2-(3,4-methylenedioxyphenyl)-4-thiazolidinecarboxylic acid of the formula of claim
 1. 24. (4R)-3-[(2S)-3-Mercapto-2-methylpropanoyl]-2-(1-napthyl)-4-thiazolidinecarboxylic acid of the formula of claim
 5. 25. (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-2-phenyl-4-thiazolidinecarboxylic acid of the formula of claim
 3. 26. (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-2-phenyl-4-thiazolidinecarboxylic acid of the formula of claim
 3. 27. (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-2-(4-methylphenyl)-4-thiazolidine carboxylic acid of the formula of claim
 3. 28. (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-2-(4-methylphenyl)-4-thiazolidine carboxylic acid of the formula of claim
 3. 29. (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-2-(2-nitrophenyl)-4-thiazolidine carboxylic acid of the formula of claim
 3. 30. (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-2-(2-nitrophenyl)-4-thiazolidine carboxylic acid of the formula of claim
 3. 31. A composition comprising a compound of any of claims 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 2 in an amount sufficient to reduce blood pressure and pharmaceutically acceptable excipient(s).
 32. A method for reducing blood pressure which comprises administering a composition comprising a compound of any of claims 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 2 and pharmaceutically acceptable excipients(s). 